U.S. patent application number 11/264432 was filed with the patent office on 2006-05-04 for methods for the removal of heavy metals.
This patent application is currently assigned to Agouron Pharmaceuticals, Inc.. Invention is credited to Yunying Fan, James Edward Saenz, Bing Shi, Jayaram Kasturi Srirangam, Shu Yu.
Application Number | 20060091067 11/264432 |
Document ID | / |
Family ID | 35517366 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060091067 |
Kind Code |
A1 |
Fan; Yunying ; et
al. |
May 4, 2006 |
Methods for the removal of heavy metals
Abstract
The present invention relates to novel compositions such as
cysteine adsorbed on solid support media and trimercaptotriazine
bound to silica gel, which are useful for the removal of heavy
metals such as palladium from organic phases. The present invention
also relates to methods of removing heavy metals by using these
compositions.
Inventors: |
Fan; Yunying; (Poway,
CA) ; Saenz; James Edward; (Kalamazoo, MI) ;
Shi; Bing; (San Diego, CA) ; Srirangam; Jayaram
Kasturi; (San Diego, CA) ; Yu; Shu; (San
Diego, CA) |
Correspondence
Address: |
AGOURON PHARMACEUTICALS, INC.
10777 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
Agouron Pharmaceuticals,
Inc.
|
Family ID: |
35517366 |
Appl. No.: |
11/264432 |
Filed: |
October 31, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60624719 |
Nov 2, 2004 |
|
|
|
Current U.S.
Class: |
210/502.1 ;
210/679; 210/688 |
Current CPC
Class: |
B01J 20/3251 20130101;
B01D 15/00 20130101; B01J 20/3255 20130101; B01J 2220/56 20130101;
B01J 20/3204 20130101; B01J 20/103 20130101; B01J 20/28083
20130101; B01J 20/28004 20130101; B01J 20/3242 20130101; B01J
2220/58 20130101; B01J 20/28073 20130101; B01D 39/2068 20130101;
B01J 20/3244 20130101 |
Class at
Publication: |
210/502.1 ;
210/679; 210/688 |
International
Class: |
B01D 39/00 20060101
B01D039/00 |
Claims
1. A composition comprising solid support media and cysteine
adsorbed thereto.
2. The composition of claim 1, wherein the solid support media is
selected from the group consisting of silica gel, silica alumina,
alumina, clay, and carbon.
3. The composition of claim 1, wherein the composition comprises
cysteine in an amount that is 0.01% or greater of the weight of the
solid support media.
4. The composition of claim 1, wherein the composition comprises
cysteine in an amount that is from 1% to 30% of the weight of the
solid support media.
5. A composition comprising trimercaptotriazine (TMT) bound to
silica gel.
6. The composition of claim 5, wherein TMT is bound to silica gel
according to the following structure ##STR10## wherein R is C.sub.1
to C.sub.8 alkyl, C.sub.2 to C.sub.8 alkenyl, or C.sub.2 to C.sub.8
alkynyl.
7. The composition of claim 6, wherein the composition comprises
TMT in an amount that is 0.01% or greater of the weight of the
silica gel.
8. The composition of claim 6, wherein the composition comprises
TMT in an amount that is from 10% to 70% of the weight of the
silica gel.
9. A method for reducing the amount of at least one heavy metal in
an organic phase, the method comprising contacting the organic
phase with the composition of any of claims 1 to 8 to afford an
organic phase wherein the amount of the at least one heavy metal is
less than in the organic phase prior to contacting with said
composition.
10. The method of claim 9, wherein the contacting step is carried
out by batch stirring.
11. The method of claim 9, wherein the contacting step is carried
out using a fixed bed reactor.
Description
FIELD OF THE INVENTION
[0001] This application claims priority to U.S. Patent Application
No. 60/624,719, filed Nov. 2, 2004, which is hereby incorporated by
reference.
[0002] The present invention relates to compositions and to methods
of using such compositions for the removal of heavy metals, such as
palladium.
BACKGROUND
[0003] Heavy metals such as palladium, nickel, tin, and copper are
widely used in industrial synthetic processes for the preparation
of a wide variety of chemical compounds. Such heavy metals are
often used as catalysts in chemical reactions. Because of their
tendency to form complexes with organic compounds, however, these
metals often remain in relevant amounts in the final product.
Because of obvious safety concerns, removal of heavy metals from
reaction products is an important aspect of chemical synthesis. In
the case of pharmacologically active compounds, or intermediates
for the preparation of pharmacologically active compounds, removal
of toxic heavy metals is particularly important.
[0004] Cysteine is a known palladium scavenger (WO 98/51646). Amino
acids such as cysteine, however, typically have low solubility in
organic solvents, which results in poor contact between the amino
acids and heavy metals in the organic phase. Accordingly, amino
acids such as cysteine are typically considered to be effective as
heavy metal scavengers in aqueous solutions only.
Trimercaptotriazine (TMT) is another known scavenger of heavy
metals such as palladium. However, because of varying solubility in
different organic solvents, the use of TMT as a heavy metal
scavenger is limited to certain chemical reactions (see Rosso, et
al. Organic Process Res. Dev. 1:311-314 (1997)).
[0005] Because of the current limitations in removing heavy metals
from organic compounds, there is a need in the art for more
efficient and more cost effective methods of heavy metal
removal.
[0006] The discussion of the background to the invention herein is
included to explain the context of the present invention. This is
not to be taken as an admission that any of the material referred
to was published, known, or part of the common general knowledge in
any country as of the priority date of any of the claims.
SUMMARY
[0007] The present invention relates to compositions useful for
removing heavy metals from an organic phase. In one embodiment, the
invention provides a composition comprising solid support media and
cysteine adsorbed thereto. In particular the solid support media is
selected from the group consisting of silica gel, silica alumina,
alumina, clay, and carbon. Still more particularly, the solid
support media is silica gel. Even more particularly, the solid
support media is silica alumina. Even more particularly, the solid
support media is alumina. Even more particularly, the solid support
media is clay. Even more particularly, the solid support media is
carbon. Still more particularly, the cysteine is L-cysteine. Still
more particularly, the cysteine is D-cysteine. Still more
particularly, the cysteine is D,L-cysteine.
[0008] In another embodiment, the invention relates to a
composition comprising solid support media and cysteine adsorbed
thereto, wherein the composition comprises cysteine in an amount
that is 0.01% or greater of the weight of the solid support media.
Even more particularly, the composition comprises cysteine in an
amount that is 0.1% or greater of the weight of the solid support
media. Still more particularly, the composition comprises cysteine
in an amount that is 0.5% or greater of the weight of the solid
support media. Still more particularly, the composition comprises
cysteine in an amount that is 1.0% or greater of the weight of the
solid support media. Still more particularly, the composition
comprises cysteine in an amount that is 5.0% or greater of the
weight of the solid support media. Still more particularly, the
composition comprises cysteine in an amount that is from 1% to 50%
of the weight of the solid support media. For example the
composition comprises cysteine in an amount that is from 1% to 30%
of the weight of the solid support media. Still more particularly,
the composition comprises cysteine in an amount that is from 5% to
30% of the weight of the solid support media.
[0009] In a further embodiment, the present invention relates to a
method for making cysteine-adsorbed solid support media comprising
contacting a solid support media with a solution comprising
cysteine, and drying the solid support media. More particularly,
the volume of cysteine solution contacted with the solid support
media is no greater than 400% of the inner pore volume of the solid
support media. More particularly, the volume of cysteine solution
contacted with the solid support media is no greater than 200% of
the inner pore volume of the solid support media. Even more
particularly, the volume of cysteine solution contacted with the
solid support media is no greater than 150% of the inner pore
volume of the solid support media. Even more particularly, the
volume of cysteine solution contacted with the solid support media
is no greater than 100% of the inner pore volume of the solid
support media. Even more particularly, the volume of cysteine
solution contacted with the solid support media is no greater than
the incipient wetness volume of the solid support media. Still more
particularly, the solid support media is silica gel. Still more
particularly, the solid support media is alumina silica. Still more
particularly, the solid support media is clay. Still more
particularly, the solid support media is carbon. Still more
particularly, the solid support media is silica gel. Still more
particularly, the cysteine is L-cysteine. Still more particularly,
the cysteine is D-cysteine. Still more particularly, the cysteine
is D,L-cysteine.
[0010] In a further embodiment, the present invention relates to a
composition prepared by any of the methods described above.
[0011] In another embodiment, the invention relates to a
composition comprising silica gel bound to trimercaptotriazine
(TMT). More particularly, the invention relates to a composition
wherein TMT is bound to silica gel according to the following
formula ##STR1## wherein R is C.sub.1 to C.sub.8 alkyl, C.sub.2 to
C.sub.8 alkenyl, or C.sub.2 to C.sub.8 alkynyl. Even more
particularly, R is ethyl.
[0012] In another embodiment, the invention relates to a
composition comprising silica gel bound to TMT, wherein the
composition comprises TMT in an amount that is 0.01% or greater of
the weight of the silica gel. In a further embodiment the
composition comprises TMT in an amount that is 0.1% or greater of
the weight of the silica gel. Even more particularly, the
composition comprises TMT in an amount that is 0.5% or greater of
the weight of the silica gel. Still more particularly, the
composition comprises TMT in an amount that is 1.0% or greater of
the weight of the silica gel. Still more particularly, the
composition comprises TMT in an amount that is 10% or greater of
the weight of the silica gel. Still more particularly the
composition comprises TMT in an amount that is 20%, 30%, 40%, 50%,
60%, 70%, or 80% of the weight of the silica gel.
[0013] In a further embodiment, the present invention relates to a
method of binding TMT to silica gel comprising reacting a
derivatized silica gel with TMT as follows ##STR2## where R is
C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.8 alkenyl, or C.sub.2 to
C.sub.8 alkynyl and X is halogen. More particularly, R is ethyl and
X is chlorine. Still more particularly, the reaction is carried out
in the presence of a base, an organic solvent, and a salt. Even
more particularly, the base is triethylamine, the organic solvent
is methanol, and the salt is potassium iodide. TMT can exist as an
un-ionized trithiol as shown above, a solid trisodium salt
(TMT-Na.sub.3, undecahydrate), and as an aqueous solution of
TMT-Na.sub.3. Accordingly, the present invention also relates to
the TMT-Na.sub.3 form bound to silica gel.
[0014] In another embodiment, the present invention relates to a
composition prepared by the methods described above.
[0015] In a further embodiment, the invention relates to a method
for reducing the amount of at least one heavy metal in an organic
phase, the method comprising contacting the organic phase with any
of the compositions described above to afford an organic phase
wherein the amount of the at least one heavy metal is less than in
the organic phase prior to contacting with said composition. More
particularly, the contacting step is carried out by batch stirring.
Still more particularly, the contacting step is carried out using a
fixed bed reactor. Even more particularly, the amount of the at
least one heavy metal in the organic phase after contacting with
said composition is less than 1000 ppm. Even more particularly, the
amount of the at least one heavy metal in the organic phase after
contacting with said composition is less than 500 ppm. Even more
particularly, the amount of the at least one heavy metal in the
organic phase after contacting with said composition is less than
300 ppm. Even more particularly, the amount of the at least one
heavy metal in the organic phase after contacting with said
composition is less than 100 ppm. Even more particularly, the
amount of the at least one heavy metal in the organic phase after
contacting with said composition is less than 50 ppm. Even more
particularly, the amount of the at least one heavy metal in the
organic phase after contacting with said composition is less than
10 ppm. Even more particularly, the amount of the at least one
heavy metal in the organic phase after contacting with said
composition is less than 1 ppm. Even more particularly, the amount
of the at least one heavy metal in the organic phase after
contacting with said composition is not greater than the amount of
said heavy metal allowed in pharmaceutical formulations by the U.S.
Food and Drug Administration. Still more particularly, in any of
the methods described above, the at least one heavy metal is
palladium. Still more particularly, in any of the methods described
above, the at least one heavy metal is tin. Still more
particularly, in any of the methods described above, the at least
one heavy metal is copper, platinum, silver, mercury, or lead.
[0016] In a further embodiment, the invention relates to a method
for reducing the amount of at least one heavy metal in an organic
phase, the method comprising contacting the organic phase with any
of the compositions described above to afford an organic phase
wherein the amount of the at least one heavy metal is reduced by at
least 50% relative to the organic phase prior to contacting with
said composition. More particularly, the amount of the at least one
heavy metal is reduced by at least 70% relative to the organic
phase prior to contacting with said composition. Still more
particularly, the amount of the at least one heavy metal is reduced
by at least 90% relative to the organic phase prior to contacting
with said composition. Even more particularly, the amount of the at
least one heavy metal is reduced by at least 95% relative to the
organic phase prior to contacting with said composition.
[0017] Unless otherwise stated, the following terms used in the
specification and claims have the meanings discussed below.
[0018] "Solid support media" refers to an insoluble material or
particle which allows ready separation from liquid phase materials
by filtration.
[0019] "L-cysteine" refers to the L stereoisomer of cysteine.
[0020] "D-cysteine" refers to the D stereoisomer of cysteine.
[0021] "D,L-cysteine" refers to a mixture of D and L stereoisomers
of cysteine.
[0022] "Cysteine-adsorbed solid support media" refers to a solid
support media comprising cysteine adsorbed thereto.
[0023] "Inner pore volume" refers to the interior cumulative open
volume that results from pores or gaps found in various solid
support media.
[0024] "Alkyl" refers to a saturated aliphatic hydrocarbon radical
including straight chain and branched chain groups. Examples of
alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl,
iso-butyl, tert-butyl, pentyl, and the like.
[0025] The term "C.sub.2-C.sub.8 alkenyl", as used herein, means an
alkyl moiety comprising 2 to 8 carbons having at least one
carbon-carbon double bond. The carbon-carbon double bond in such a
group may be anywhere along the 2 to 8 carbon chain that will
result in a stable compound. Such groups include both the E and Z
isomers of said alkenyl moiety. Examples of such groups include,
but are not limited to, ethenyl, propenyl, butenyl, allyl, and
pentenyl.
[0026] As used herein, the term "C.sub.2-C.sub.8 alkynyl" means an
alkyl moiety comprising from 2 to 8 carbon atoms and having at
least one carbon-carbon triple bond. The carbon-carbon triple bond
in such a group may be anywhere along the 2 to 8 carbon chain that
will result in a stable compound. Examples of such groups include,
but are not limited to, ethyne, propyne, 1-butyne, 2-butyne,
1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne.
[0027] "Halogen" and/or "halide" refer to fluorine, chlorine,
bromine or iodine.
[0028] "Organic phase" refers to a phase that is immiscible with an
aqueous phase.
[0029] "Heavy metal" refers to any element in a block of the
periodic table defined by Groups 3 to 16 and Periods 4 and
higher.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 shows a schematic diagram of a heavy metal removal
process using a fixed-bed reactor.
[0031] FIG. 2 shows a comparison of the UV-vis signal during the
palladium removal process using a fixed-bed reactor. The feed
concentration was kept constant.
[0032] FIG. 3 shows the profiles of palladium concentration as a
function of recirculation time in the fixed-bed reactor process
when 5 equivalents of silca gel were used.
DETAILED DESCRIPTION
[0033] In order to improve the efficiency and cost effectiveness of
heavy metal removal by cysteine in organic solvents, the present
invention provides a composition comprising solid support media and
cysteine adsorbed thereto. To overcome the problems associated with
low solubility of cysteine in organic solvents when removing heavy
metals, adsorbing cysteine to a solid support media such as silica
gel was contemplated. Use of a solid support also facilitates
separation of the heavy metal from the organic phase, as opposed to
other separation procedures such as extraction. The present
invention relates to the discovery that when a heavy metal
scavenger such as cysteine is adsorbed uniformly to a solid support
media, the surface area of exposed cysteine can be maximized. This
cysteine-adsorbed solid support media can then be contacted with an
organic phase containing at least one heavy metal, which
subsequently allows greater contact between cysteine and a heavy
metal, despite the low solubility of cysteine in the organic phase.
Thus, use of this cysteine-adsorbed solid support media is able to
improve the efficiency and cost-effectiveness of the heavy metal
removal process.
[0034] The compositions of the present invention can be prepared
using a variety of solid support media. Suitable solid support
media are known to those of skill in the art and include those that
are made of an inert inorganic matrix, which eliminates issues
associated with swelling and solvent incompatibility. Suitable
solid support media should also be amenable to drying and filtering
from the organic phase. Use of a suitable solid support media is
desirable since it can be added directly to the reaction mixture or
used in a column to selectively remove heavy metals. Use of solid
support media in this way also helps ensure that the process will
be scalable without protocol modifications. Examples of suitable
solid support media are known to those skilled in the art and
include, but are not limited to, silica gel, silica alumina,
alumina, clay, zeolites, titania, zirconia sulfate,
alumino-phosphate, and carbon, which are all readily available from
commercial sources. Silica gel involves a solid amorphous silicic
acid which is known for use as an adsorption agent for gas, vapor
and liquids and can be made with pores of different diameter.
Silica gels exhibit a large inner surface, which may range up to
800 m.sup.2/g, to absorb liquid. Numerous grades of silica gel of
varying mesh and pore size are commercially available and are known
to those in the art. For example, Merck 10180 is a 70-230 mesh
silica gel with a mean pore diameter of 40 angstroms. Merck 10184
is a 70-230 mesh silica gel with a mean pore diameter of 100
angstroms. Merck 10185 is a 35-70 mesh silica gel with a mean pore
diameter of 100 angstroms. Merck 10181 is a 35-70 mesh silica gel
with a mean pore diameter of 40 angstroms. Davisil 643 is a 200425
mesh silica gel with a mean pore diameter of 150 angstroms.
[0035] Although any type of silica gel can be used within the
context of the present invention, preferred grades of silica gel
include those that are less brittle such as Merck 10180. Numerous
grades of silica alumina are also known to those in the art and are
commercially available. For example, silica alumina grade 135 is
available from commercial suppliers such as Aldrich. Clays suitable
as solid support media are also known to those in the art and
consist of layered materials with spaces between the layers that
can absorb water molecules or positive and negative ions and
undergo exchange interaction of these ions with solvents. Clays
have very unique properties. When they are dried, for example, the
molecules or ions between the layers can come out, the gaps between
the layers can close and the layer stack can shrink significantly.
Examples of clays include, but are not limited to laponite,
bentonite or hectorite. Other suitable solid support media such as
alumina, zeolites, titania, zirconia sulfate, alumino-phosphate,
and carbon are well known to those in the art.
[0036] The amount of cysteine adsorbed to the solid support media
can vary from certain lower limits to certain upper limits, where
the amount of cysteine adsorbed to the solid support media can be
stated in terms of a weight percentage of the weight of solid
support media. This amount of cysteine adsorbed to the solid
support media is also referred to as the loading percentage. The
present invention contemplates a lower limit of cysteine loading of
0.01%, or 0.1%, or 0.5%, or 1%. For example, if 10.0 g of silica
gel is used as the solid support media, the contemplated lower
limits of cysteine adsorbed thereto would correspond to 0.001 g,
0.01 g, 0.05 g, or 0.1 g, respectively. The present invention also
contemplates an upper limit of cysteine loading of 100%, or 50%, or
40%, or 30%, or 20%, or 10%. Again, for example, if 10.0 g of
silica gel is used as the solid support media, the contemplated
upper limits of cysteine adsorbed thereto would correspond to 10.0
g, 5.0 g, 4.0 g, 3.0 g, 2.0 g, or 1.0 g, respectively. Furthermore,
the invention contemplates cysteine adsorbed on the solid support
media in an amount that ranges from any of the above lower limits
to any of the above upper limits. The optimal loading of cysteine
on a particular solid support media will vary depending on the
chemical species involved and the specific treatment procedure that
is used.
[0037] Cysteine exists in two different stereoisomers, designated
as D-cysteine and L-cysteine. Accordingly, cysteine can exist as
either relatively pure D-cysteine, relatively pure L-cysteine, or a
mixture of the two isomers, which can be designated as
D,L-cysteine. When cysteine is adsorbed to silica gel and used to
remove palladium from an organic phase, there is an insignificant
difference in the removal efficiency between L-cysteine and
D,L-cysteine. Accordingly, since L-cysteine is significantly
cheaper than D,L-cysteine, use of L-cysteine provides a more cost
effective means to reduce levels of palladium in an organic
phase.
[0038] The process of coating onto porous solid support media is
mechanistically complex. Several factors can influence the coating
process, including the solid support surface area, the structure
and composition of the solid support media, the temperature, the
concentration of the chemical species being adsorbed thereto, and
the drying conditions (see, e.g. Ertl et al., Handbook of
Heterogeneous Catalysis, John Wiley & Sons, (April 1997); Ruiz
et al. Separation Science and Technology 37:2143 (2002)).
Challenges associated with adsorbing to a porous solid media
include inconsistent loading from batch to batch, structural
changes to the solid support media (e.g. surface area, pore
volume), aggregation, and non-uniform coating. One embodiment of
the present invention relates to a method for making
cysteine-adsorbed solid support media comprising contacting a solid
support media with a solution comprising cysteine, and then drying
the solid support media.
[0039] Several methods of contacting the cysteine with the solid
support media are contemplated in the present invention. For
example, one method known as evaporation coating involves adding a
solution of cysteine to a fixed vessel that contains the solid
support media followed by stirring. This mixture is then dried with
heating conditions under vacuum. Another coating procedure known as
precipitation coating involves adding a cysteine solution to a
fixed vessel that contains the solid support media, followed by
stirring. A cysteine precipitating agent, such as an organic
solvent, is then added to the mixture, which causes any
non-adsorbed cysteine to precipitate. The slurry is then filtered
and the wet cake is dried using heating conditions under
vacuum.
[0040] Another method of contacting the cysteine solution with the
solid support media is known as impregnation coating. This method
involves contacting the solid support media with a cysteine
solution by wetting the solid support media through diffusion. This
can be accomplished, for example, by adding a volume of cysteine
solution that is equal to the incipient wetness volume of the solid
support media to a fixed vessel containing the solid support media.
Because the adsorbtion of cysteine to the solid support media is
accomplished primarily through diffusion, stirring or mixing is not
necessary. The resulting impregnated solid support media can then
be dried using heating conditions under vacuum.
[0041] The amount of cysteine solution that is contacted with a
solid support media using the impregnation method can be stated in
terms of the incipient wetness volume of the solid support media.
The incipient wetness volume is specific for each solid support
media, and can vary depending on several factors including the
manufacturing procedure. For a particular solid support media, the
incipient wetness volume indicates the amount of solution required
to saturate the inner pore volume. The incipient wetness volume of
a given solid support media can be determined by measuring the
minimum amount of solution required to be added to the solid
support media so that a paste is formed. The incipient wetness
volume is typically 50 to 70% greater than the inner pore volume of
the solid support media.
[0042] In one embodiment of the invention is a method for making
cysteine-adsorbed solid support media by contacting the solid
support media with an amount of cysteine solution that is not
greater than 200% of the inner pore volume. For example, silica
gels typically have an inner pore volume ranging from 0.5 to 1.5
mL/g. For example, if the inner pore volume of a particular silica
gel is 0.7 mL/g, cysteine solution would be contacted with 1.0 g of
the silica gel in an amount not greater than 1.4 mL. Similarly,
another aspect of the invention is a method for making
cysteine-adsorbed solid support media by contacting the solid
support media with an amount of cysteine solution that is not
greater than 150% of the inner pore volume. Using 1.0 g of the same
silica gel as above with a corresponding inner pore volume of 0.7
mL/g, cysteine solution would be contacted with 1.0 g of the silica
gel in an amount not greater than 1.05 mL.
[0043] Once the cysteine solution has been contacted with the solid
support media, the resulting mixture can be dried to remove any
liquid medium. The present invention contemplates any suitable
means of drying. Suitable drying conditions usually comprise an
elevated temperature and/or a reduced pressure. In general,
techniques for drying are known in the art, including heating to
promote evaporation of the liquid medium, or simply drying in air.
The drying step generally removes a significant portion of the
liquid medium from the mixture; however, there still may be a minor
portion (e.g., 10% or less by weight) of the liquid medium present
in the dried mixture. Typical drying conditions include
temperatures ranging from room temperature to over 200.degree. C.,
typically between 50.degree. C. to 150.degree. C. The amount of
time for drying to occur may range from about 30 minutes to more
than several days. Suitable methods of drying and corresponding
equipment are well known to those of skill in the art. Examples of
such suitable means of drying include, but are not limited to,
drying in a pan oven under vacuum, use of an agitated dryer, use of
a tumble dryer, or use of a rotary evaporator.
[0044] When adsorbing cysteine on silica gel on small scales (e.g.
less than 5 g silica gel) a vacuum pan dryer provides sufficient
drying conditions. Furthermore, movement of the silica gel is
generally not required due to the uniform heating in the small
sample size. At larger scales (e.g. 50 g or more silica gel),
however, movement of the silica gel is generally necessary to
prevent cysteine/water channeling between particles. A rotary
evaporator or tumble dryer can be used at large scales to avoid
such problems. These types of drying not only help ensure a uniform
distribution of cysteine on silica gel, but can also reduce the
drying time due to better heat and mass transfer compared with a
pan dryer.
[0045] In the methods discussed above, the cysteine solution can be
an aqueous solution. The cysteine solution can also contain HCl,
which is useful to prevent the oxidation of cysteine to cystine.
For example, the cysteine solution can be a 0.01 N HCl solution.
The concentration of cysteine in the solution can vary depending on
the incipient wetness volume of the solid support media being used
and the desired cysteine loading percentage on the solid support
media. For example, if a 10% cysteine loading on silica gel is
desired, given the amount of silica gel to be used, and the
corresponding incipient wetness volume, the cysteine concentration
can be adjusted to the appropriate level in order to achieve a 10%
loading. To dissolve cysteine in water, the temperature can be
increased from room temperature to 50.degree. C. and stirred until
cysteine is dissolved. During stirring, the solution can be sealed
or kept under an inert atmosphere to prevent oxidation of cysteine.
As discussed previously, cysteine can exist as either D-cysteine,
L-cysteine, or a mixture of the two isomers, which can be
designated as D,L-cysteine. Once the cysteine has been adsorbed
onto the solid support media, it should be stored at room
temperature in a sealed container.
[0046] The present invention also relates to a composition
comprising trimercaptotriazine (TMT) bound to silica gel. Because
of the varying solubility of TMT in different solvents, binding TMT
to a solid support media such as silica gel provides improved
contact with heavy metals, regardless of the solvent systems being
used. TMT can be bound to silica gel through a linker as shown in
the following structure ##STR3## wherein R is C.sub.1 to C.sub.8
alkyl, C.sub.2 to C.sub.8 alkenyl, or C.sub.2 to C.sub.8 alkynyl,
including straight chain and branched chain groups. Examples
include, but are not limited to, methyl, ethyl, propyl, butyl,
pentyl, isobutyl, tert-butyl, ethenyl, propenyl, butenyl, allyl,
pentenyl, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne,
2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne. TMT is commercially
available as the un-ionized trithiol, as a solid trisodium salt
(TMT-Na.sub.3, undecahydrate), and as an aqueous solution of
TMT-Na.sub.3. Thus, TMT-Na.sub.3 can also be bound to silica gel in
a manner analogous to that shown above for TMT.
[0047] TMT or TMT-Na.sub.3 can be bound to silica gel by reacting a
derivatized silica gel with TMT or TMT-Na.sub.3, according to the
following reaction scheme: ##STR4## where R and X are as defined
above. In particular, alkyl-halide silica gels such as chloride-3
silica gel (Silicycle) are commercially available. The binding
reaction can take place under conditions that include a base, an
organic solvent, and a salt. Suitable bases include bases with a
pKa greater than 7. Typical bases include but are not limited to
potassium carbonate, sodium carbonate, cesium carbonate, cesium
hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium
phenoxide, cyclohexylamine, diisopropylethylamine, trimethylamine,
triethylamine, and the like, or mixtures thereof. Suitable organic
solvents include alcohols such as ethanol and methanol, dimethyl
formamide, acetonitrile, tetrahydrofuran, toluene, xylenes,
dimethylethyleneglycol, and the like, or mixtures thereof. Suitable
salts include any iodine salt, such as potassium iodine. Other
appropriate general reaction conditions, which are well known to
those of skill in the art, may include stirring, heating to reflux,
stirring at reflux under nitrogen atmosphere, and cooling.
[0048] The amount of TMT bound to silica gel can vary from certain
lower limits to certain upper limits, where the amount of TMT
bounded to silica gel can be stated in terms of a weight percentage
of the weight of silica gel. This amount of TMT bound to the silica
gel is also referred to as the loading percentage. The present
invention contemplates a lower limit of TMT loading of 0.01%, or
0.1%, or 0.5%, or 1%. For example, if 10.0 g of silica gel is used,
the contemplated lower limits of TMT bound thereto would correspond
to 0.001 g, 0.01 g, 0.05 g, or 0.1 g, respectively. The present
invention also contemplates an upper limit of TMT loading of 100%,
or 50%, or 40%, or 30%, or 20%, or 10%. Again, for example, if 10.0
g of silica gel is used, the contemplated upper limits of TMT bound
thereto would correspond to 10.0 g, 5.0 g, 4.0 g, 3.0 g, 2.0 g, or
1.0 g, respectively. Furthermore, the invention contemplates TMT
bound to silica gel in an amount that ranges from any of the above
lower limits to any of the above upper limits. The optimal loading
of TMT on a particular silica gel will vary depending on the
chemical species involved and the specific treatment procedure that
is used.
[0049] The compositions described above can be used to reduce the
amount of at least one heavy metal in an organic phase. This can be
done by contacting the organic phase with any of the
cysteine-adsorbed solid support media or TMT-CH.sub.2--R-silica gel
compositions described herein. Contacting the cysteine-adsorbed
solid support media or TMT-CH.sub.2--R-silica gel compositions with
the organic phase can be done using any suitable method that allows
these compositions to come into contact with the organic phase.
Examples of this contacting step include, but are not limited to,
batch stirring and use of a fixed bed reactor. The process of batch
stirring is well known and involves adding the components to be
contacted with each other to a constant volume vessel, followed by
any suitable means of stirring. Addition of the components can be
done simultaneously or individually in any order. Components that
are added to the vessel in a batch stirring process remain in the
vessel until the reaction is complete. Use of fixed-bed reactors to
contact various components is also well known to those in the art
and involves passing a first component through a column containing
a second component. The first component is allowed to enter and
then exit the column, while the second component remains in the
column throughout the reaction process. Several types of fixed-bed
reactors are well known, and include tube reactors and
shell-and-tube reactors. The terms "tube reactor" and
"shell-and-tube reactor" refer to parallel assemblies of many
channels in the form of tubes, where the tubes can have any cross
section. The tubes are fixed in space relative to one another,
preferably have a spacing between them, and are preferably
surrounded by a jacket (shell) which encloses all the tubes. In
this way, for example, a heating or cooling medium can be passed
through the shell so that all tubes are uniformly heated/cooled.
Cooling mediums that can be used in such fixed-bed reactors include
water, or a mixture of ethylene glycol and water. For example, a
mixture of 30% ethylene glycol and water can be used for cooling
purposes.
[0050] By employing the methods described above, the level of heavy
metal in an organic phase can be reduced. For example, the level of
a heavy metal can be reduced to an amount that is less than 500
ppm, less than 300 ppm, less than 100 ppm, less than 10 ppm, or
less than 1 ppm. Heavy metals that can be reduced by employing
these methods include palladium, copper, tin, platinum, silver,
mercury and lead. The level of reduced heavy metal in an organic
phase will depend on several factors including the concentration of
heavy metal originally present in the organic phase, the contact
time between the organic phase and the compositions for removal of
heavy metals described herein, the volume of the treated organic
phase, the method of contacting (e.g. use of a fixed bed reactor,
or batch stirred), the loading of the heavy metal scavenger on the
solid support media, and the amount of loaded solid support media
used. One of skill in the art will recognize that the above
reaction conditions can be modified to achieve different levels of
reduced heavy metal in an organic phase.
[0051] Regulatory agencies, such as the U.S. Food and Drug
Administration (USFDA), often require levels of specific heavy
metals to be below certain upper limits in food, pharmaceutical
formulations, or other substances that humans can be exposed to.
Levels of heavy metals that are acceptable in a pharmaceutical drug
substance can have significant variation, depending on factors such
as the dosage, mode of administration, treatment population and
duration of treatment, known toxicity of the metal in question, and
the ability of manufacturing processes to control the heavy metal
levels. The most common test for heavy metal levels is described in
the U.S. Pharmacopoeia (USP), with similar methods reported in the
European Pharmacopoeia (EP) and Japan Pharmacopoeia (JP). By
employing the methods described above, the level of heavy metal in
an organic phase can be reduced to an amount that is not greater
than the amount of said heavy metal allowed by a regulatory agency
such as the USFDA. Allowable levels of specific heavy metals for
specific situations and conditions are published and are readily
available from the various regulatory agencies.
EXAMPLES
[0052] In the examples described below, unless otherwise indicated,
all temperatures are in degrees Celsius (.degree. C.), and all
parts and percentages are by weight. Various starting materials and
other reagents were purchased from commercial suppliers such as
Aldrich Chemical Company and EM science, and were used without
further purification, unless otherwise indicated.
[0053] The examples and preparations provided below further
illustrate and exemplify the methods and compositions of the
present invention. It should be understood that the scope of the
present invention is not limited in any way by the scope of the
following examples.
[0054] As used in the examples below, TMT refers to
trimercaptotriazine, DCM refers to dichloromethane, ACN refers to
acetonitrile, MeOH refers to methanol, Ac refers to acetyl, THF
refers to thetrahydrofuran, min refers to minutes, ppm refers to
parts per million, and vol refers to volume.
Example 1
Process for the Preparation of 10% Cysteine on Silica Gel
[0055] Silica gel with a cysteine loading of 10% was prepared
according to the following procedure. 3000 g of Merck 10180 silica
gel (70-230 mesh; mean pore diameter 40 angstroms; surface area 692
m.sup.2/g; pore volume 0.724 mL/g; incipient wetness volume 1.18 mL
based on 1.1 g sample) were added to a 22 L Rotovap rotary
evaporator while rotating. A solution of L-cysteine (300 g) in
water (3300 mL) was then added to the rotary evaporator. The
resulting mixture was evaporated under house vacuum (approx. 65
mbar) at a bath temperature of 50.degree. C. The silica gel was
continued drying for 24 hours, or until the moisture content as
measured by a Mettler Toledo Karl Fisher titrator (DL31) was
<4%.
Example 2
Process for Palladium Removal Treatment
[0056] To test the cysteine-adsorbed silica gel as prepared in
Example 1, a palladium contimainted organic phase, resulting from
the following chemical reaction, was used. ##STR5## The reaction
shown above is a reaction step discussed in detail in a U.S.
provisional patent application entitled Methods for Preparing
Indazole Compounds, U.S. 60/624,801 filed on Dec. 14, 2004, which
is incorporated herein by reference. To carry out the above
reaction, a 2 L three-neck flask, equipped with a mechanical
stirrer, temperature probe, and condenser, was charged with
compound 1 (48.8 g), compound 2 (50.0 g),
di-t-butylphosphinobiphenyl (2.42 g), sodium t-butoxide (19.30 g),
and toluene (500 mL) under argon atmosphere. The resulting slurry
was evacuated and backfilled with argon. The evacuation backfill
procedure was repeated three times. The flask was then charged with
tris(dibenzylideneacetone) dipalladium under a blanket of argon.
The reaction mixture was then heated to reflux (102.degree. C.) and
stirred for 18 hours under argon. The reaction was monitored by
HPLC. After 18 hours, HPLC indicated 10.78% @ 4.69 min (compound
2), 5.11% @ 5.34 min (compound 1), 26.85% @ 5.97 min (toluene), and
49.09% @ 6.15 min (compound 3). Due to the use of the palladium
catalyst, the final compound 3 showed a palladium content of 5000
ppm. To reduce the level of palladium, the reaction was allowed to
cool to 40.degree. C., then charged with THF (500 mL), followed by
10% cysteine-adsorbed silica gel (250 g) as prepared in Example 1.
The resulting mixture was stirred at room temperature for 24 hours.
The mixture was then filtered through a course-fritted funnel with
a pad of Celite.TM. 545 (100 g). The resulting pad was washed with
THF (500 mL). A sample from the combined filtrate was found to have
530 ppm palladium. HPLC analysis following the cysteine-adsorbed
silica gel treatment indicated 12.28% @ 4.19 min (compound 2),
7.56% @ 4.88 min (compound 1), 58.95% @ 5.83 min (compound 3), and
8.72% @ 6.84 min (unknown). The combined filtrate was concentrated
leaving 1000 mL of solution that was stirred with 10%
cysteine-adsorbed silica gel (250 g) for 48 hours. The mixture was
filtered through a course-fritted funnel with a pad of Celite.TM.
545 (100 g). The resulting pad was rinsed with THF (1000 mL). The
combined filtrate was concentrated leaving 75.67 g of yellow foam
of compound 3. The sample was found to contain 92 ppm palladium.
HPLC following this second treatment with cysteine-adsorbed silica
gel indicated 13.37% @ 4.68 min (compound 2), 6.96% @ 5.33 min
(compound 1), 59.29% @ 6.14 min (compound 3), and 8.23% @ 6.95 min
(unknown). The HPLC method used involved the following conditions:
Phenomenex Prodigy ODS-3 column, 50.times.4.6 mm, 5 .mu.m; UV
detector, 254 nm; solvents used were 0.025 M aqueous
NH.sub.4OAc/ACN; gradient was 15-90% ACN over 5.25 min, hold 90%
ACN 2.25 min; Flow rate was 1.0 mL/min; retention times were 4.69
min (compound 2), 5.34 min (compound 1), 5.97 min (toluene), and
6.15 min (compound 3).
Example 3
Process for the Preparation of 5% Cysteine on Silica Gel
[0057] Three different types of silica gel with a D,L-cysteine
loading of 5% were prepared according to the following procedure. 5
g of the first type of silica gel (Merck Type 10180, with a inner
pore volume of 0.724 mL/g) was wetted with 5.36 mL (the incipient
wetness volume of Merck Type 10180 silica gel) of D,L-cysteine
solution (0.25 g cysteine in 0.01N HCl). 5 g of the second type of
silica gel (Merck Type 10181) was wetted with 8.5 mL (the incipient
wetness volume of Merck Type 10181 silica gel) of D,L-cysteine
solution (0.25 g cysteine in 0.01N HCl). 5 g of the third type of
silica gel (Davisil 643) was wetted with 9.75 mL (the incipient
wetness volume of Davisil 643 silica gel) of D,L-cysteine solution
(0.25 g cysteine in 0.01N HCl). No external mixing was applied to
the mixtures. Each silica gel was wetted completely by diffusion.
The impregnated silica gels were then dried in a pan oven at
50.degree. C. and full vacuum overnight. Using a polarized
microscope, virtually no cysteine crystals were observed on any of
the silica gels, indicating that aggregation of cysteine had not
occurred during the adsorption process.
Example 4
Use Tests for Cysteine on Silica Gel Coated by the Impregnation
Procedure
[0058] To test the cysteine-adsorbed silica gels as prepared in
Example 3, a palladium contaminated organic phase, resulting from
the following chemical reaction as described in Example 2, was
used. ##STR6##
[0059] The reaction shown above is a reaction step discussed in
detail in a U.S. provisional patent application entitled Methods
for Preparing Indazole Compounds, U.S. 60/624,801, filed on Dec.
14, 2004, which is incorporated herein by reference. The coupling
reaction shown above uses a palladium catalyst to couple compounds
1 and 2. Because palladium was used in the reaction step, the
resulting compound 3 was contaminated with palladium (5000 ppm).
About 200 mg of compound 3 was first dissolved in 25.times. volume
THF in a flask. Several types of cysteine-adsorbed silica gel
(shown in the table below and prepared as described in Examples 1
and 3) were each tested for their ability to reduce palladium
levels. 5-weight equivalent of the silica gel (with 5% cysteine
loading) was then added to the flask containing compound 3. The
mixture was stirred in a sealed flask under room temperature
overnight. The slurry was filtered using a Whatman.TM. 0.2 .mu.m
PTFE syringe filter. The liquid phase was then evaporated to
dryness in a vacuum oven to yield the treated compound 3 for
palladium content analysis. Measurement of the palladium content
was performed using an inductively coupled plasma (ICP) analysis,
performed by Galbraith Laboratory, Inc. (Knoxville, Tenn.). The
results for each of the cysteine-adsorbed silica gels are shown in
the following table. TABLE-US-00001 Palladium Palladium content
content Amount of before after Cysteine Compound treatment
treatment Silica Gel Type 3 (mg) (ppm) (ppm) Merck 10180 D, L 205.0
5000 220 Merck 10180 D, L 205.8 5000 280 Merck 10180 L 207.2 5000
280 Merck 10184 D, L 202.5 5000 218 Davisil 643 D, L 207.9 5000
240
Example 5
Testing for Optimum Cysteine Loading
[0060] The efficiency of cysteine on silica gel can be influenced
by its loading. For a certain compound and a certain treatment
procedure, there will be a loading where the cysteine on silica gel
reaches its optimum efficiency in removing heavy metals such as
palladium. Silica gels with loading percentages ranging from 1 to
30% were used in the palladium removal process described in Example
4. The results, shown in the table below, indicate that a 5%
cysteine loading is optimal for the particular compound (compound
3), and for the particular palladium removal treatment as described
in Example 4. It should be noted that the optimal loading
percentage can vary depending on the particular compound being
treated and the particular treatment process that is used.
TABLE-US-00002 Palladium Palladium Content Content Cysteine Amount
of Before After Loading Cysteine Compound Treatment Treatment (%)
Type 3 (mg) (ppm) (ppm) 1 L 197.9 5000 410 3 L 205.6 5000 440 5 L
207.2 5000 280 5 D, L 205.8 5000 280 10 L 207.3 5000 451 10 L 501.4
5000 413 15 D, L 201.9 5000 360 30 D, L 200.7 5000 400
Example 6
Process for the Preparation of TMT-Silica Gel
[0061] Trimercaptotriazine (TMT) can be bound to silica gel
according to the following reaction. ##STR7##
[0062] Four different procedures were used to prepare TMT-silica
gel, labeled A-D. A) A 22 L three-neck flask equipped with a
mechanical stirrer and a temperature probe was charged with MeOH
(8000 mL), TMT (515 g), triethylamine (3750 mL), chloride-3 silica
gel (1020 g, SiliCycle), and potassium iodide (240 g) while
stirring under nitrogen atmosphere. The resulting slurry was
stirred while heating to reflux (64.degree. C.). The reaction was
then stirred at reflux for 48 hours under nitrogen atmosphere. The
heat was removed and the reaction was allowed to stir while cooling
to 40.degree. C. The mixture was filtered through course fritted
filter under vacuum. The resulting solids were washed with THF
(8L), 2N HCl (8L), water (4L), and then THF (4L). The solids were
then transferred to a drying dish and dried under house vacuum for
48 hours at 40.degree. C. B) A 22 L three-neck flask equipped with
a mechanical stirrer and a temperature probe was charged with MeOH
(5 vol/g chloride-3 silica gel), TMT (2.0 eq.), triethylamine (5
vol/g chloride-3 silica gel), chloride-3 silica gel (25.0 g,
SiliCycle), and potassium iodide (1 eq.) while stirring under
nitrogen atmosphere. The resulting slurry was stirred while heating
to reflux (68.degree. C.). The reaction was then stirred at reflux
for 18 hours under nitrogen atmosphere. The heat was removed and
the reaction was allowed to stir while cooling to room temperature.
The mixture was filtered through course fritted filter under
vacuum. The resulting solids were washed with 2N HCl (200 mL), then
THF (400 mL). This washing procedure was repeated once. The
resulting wet solids were then dried for 3 days at 22.degree. C.
under vacuum. C) A 22 L three-neck flask equipped with a mechanical
stirrer and a temperature probe was charged with MeOH (7 vol/g
chloride-3 silica gel), TMT (2.0 eq.), triethylamine (3 vol/g
chloride-3 silica gel), chloride-3 silica gel (50.0 g, SiliCycle),
and potassium iodide (1 eq.) while stirring under nitrogen
atmosphere. The resulting slurry was stirred while heating to
reflux (68.degree. C.). The reaction was then stirred at reflux for
42 hours under nitrogen atmosphere. The heat was removed and the
reaction was allowed to stir while cooling to room temperature. The
mixture was filtered through course fritted filter under vacuum.
The resulting solids were washed with THF (400 mL), 2N HCl (400
mL), then THF (400 mL). The resulting wet solids were then dried
for 18 hours at 40.degree. C. under vacuum. D) A 22 L three-neck
flask equipped with a mechanical stirrer and a temperature probe
was charged with MeOH (7 vol/g chloride-3 silica gel), TMT (2.0
eq.), triethylamine (3 vol/g chloride-3 silica gel), chloride-3
silica gel (200 g, SiliCycle), and potassium iodide (1 eq.) while
stirring under nitrogen atmosphere. The resulting slurry was
stirred while heating to reflux (68.degree. C.). The reaction was
then stirred at reflux for 42 hours under nitrogen atmosphere. The
heat was removed and the reaction was allowed to stir while cooling
to room temperature. The mixture was filtered through course
fritted filter under vacuum. The resulting solids were washed with
THF (1500 mL), 2N HCl (1500 mL), water (500 mL), then THF (1000
mL). The resulting wet solids were then dried for 60 hours at
40.degree. C. under vacuum.
Example 7
Palladium Removal Using TMT-Slica Gel
[0063] To test the ability of the TMT-silica gels as described in
Example 6, a palladium contaminated organic phase, resulting from
the following chemical reaction, was used. ##STR8##
[0064] This chemical reaction is an intermediate step in a
synthetic reaction scheme described in detail in a U.S. provisional
patent application entitled Methods for Preparing Indazole
Compounds, U.S. 60/624,575, filed on Nov. 2, 2004, which is
incorporated herein by reference. The coupling reaction shown above
uses a palladium catalyst to couple compounds 4 and 5. Because
palladium was used in this reaction step, the resulting compound 6
was contaminated with palladium (865 ppm). The general treatment
condition used to remove palladium involved stirring the crude
residue of compound 6 with TMT-silica gel, followed by filtering
through silica gel, then elution with DCM. The resulting compound
was then evaporated and tested for residual palladium. Several
different treatment conditions, using several different TMT-silica
gels as prepared in Example 6 were used. The specific palladium
treatment conditions used and the resulting palladium levels after
treatment are shown in the table below. TABLE-US-00003 Palladium
Content TMT-Silica After Treatment Gel Used Treatment Conditions
(ppm) Example 6-B TMT-silica gel (5 wt. eq.); <13 DCM (30 vol.),
evaporated for 18 hours at 23.degree. C. Example 6-B TMT-silica gel
(1 wt. eq.); 23 DCM (20 vol.), evaporated for 18 hours at
23.degree. C. Example 6-B TMT-silica gel (3 wt. eq.); <13 DCM
(20 vol.), evaporated for 18 hours at 23.degree. C. Example 6-C
TMT-silica gel (3 wt. eq.); 1.5 DCM (20 vol.), filtered through
silica gel, then evaporated for 18 hours at 23.degree. C. Example
6-D TMT-silica gel (3 wt. eq.); <6 DCM (20 vol.), filtered
through silica gel, then evaporated for 18 hours at 23.degree. C.
Example 6-A TMT-silica gel (3 wt. eq.); 3 DCM (20 vol.), filtered
through silica gel, then evaporated for 18 hours at 23.degree.
C.
Example 8
Palladium Removal Using TMT-Silica Gel
[0065] To further test the ability of the TMT-silica gels as
described in Example 6, the palladium contaminated organic compound
shown below was used. ##STR9##
[0066] Synthetic routes to prepare compound 7 using palladium are
described in detail in two U.S. provisional patent applications,
both entitled Methods for Preparing Indazole Compounds, U.S.
60/624,635 and U.S. 60/624,575, both filed on Nov. 2, 2004, which
are each incorporated herein by reference. The general treatment
condition used to remove palladium involved stirring a solution of
compound 7 with TMT-silica gel, followed by filtration through
Celite.TM., followed by evaporation and precipitation to give
compound 7 with reduced palladium levels. Because of the poor
solubility of compound 7, different solvent systems were used and
found to give different efficiencies in the removal of palladium.
Several different treatment conditions, using several different
TMT-silica gels as prepared in Example 6 were used. The specific
palladium treatment conditions used and the resulting palladium
levels after treatment are shown in the table below. In all cases,
the palladium content before treatment was 1100 ppm. TABLE-US-00004
Palladium Content TMT-Silica Gel After Treatment Used Treatment
Conditions (ppm) Example 6-D A solution in THF, water, and 2N HCl
(2 eq.) was stirred for 191 18 hours with TMT-silica gel (3 wt.
eq.), then filtered through Celite .TM. and evaporated. Example 6-D
A solution of acetic acid (5 vol.) was passed through a pad of 192
TMT-silica gel (3 wt. eq.) over Celite .TM.. The pad was washed
with THF and the combined filtrate was evaporated leaving a slurry
of product in acetic acid. The product was filtered and dried.
Example 6-D A solution of MeOH (5 vol.) and acetic acid (5 vol.)
was 6 passed through a pad of TMT-silica gel (3 wt. eq.) over
Celite .TM.. The pad was washed with MeOH and the combined filtrate
was evaporated then precipitated from toluene, filtered, and dried.
Example 6-D A solution of MeOH (5 vol.) and acetic acid (5 vol.)
was 24 passed through a pad of TMT-silica gel (3 wt. eq.) over
Celite .TM.. The pad was washed with MeOH andn the combined
filtrate was evaporated, leaving acetic acid mixture, filtered and
dried. Example 6-D A solution of water (5 vol.) and acetic acid (5
vol.) was stirred 8.6 with TMT-silica gel (3 wt. eq.) then filtered
over Celite .TM.. The pad was washed with MeOH and the combined
filtrate was evaporated and dried. Example 6-D A solution of water
(5 vol.) and acetic acid (5 vol.) was stirred 20 with TMT-silica
gel (3 wt. eq.) then filtered over Celite .TM.. The pad was washed
with MeOH and the combined filtrate was evaporated leaving acetic
acid solution, then neutralized with NaOH, then filtered and dried.
Example 6-A A solution of water (5 vol.) and acetic acid (5 vol.)
was stirred 6 with TMT-silica gel (3 wt. eq.) then filtered over
Celite .TM.. The pad was washed with MeOH and the combined filtrate
was evaporated then precipitated from xylenes, filtered and
dried.
Example 9
Palladium Removal Using TMT-Silica Gel
[0067] To further test the ability of the TMT-silica gels as
described in Example 6, the palladium contaminated (4900 ppm)
organic compound 3, as described in Example 4, was used. A solution
of compound 3 in THF was stirred for 18 hours with the TMT-silica
gel (5 wt. eq.) as described in Example 6-B, then filtered through
silica gel, eluted with THF, and evaporated. The resulting
palladium level following this treatment was 176 ppm.
Example 10
Palladium Removal Tests
[0068] Several different palladium scavengers were compared for
their ability to remove palladium. Compound 3 as discussed above in
Example 4, was used in these tests. The initial level of palladium
in a solution containing compound 3 was 6207 ppm. The palladium
scavengers were prepared as discussed in the above Examples. In
each case, 5 weight equivalents of the palladium scavenger was
added to the palladium contaminated solution of compound 3 and
stirred for 20 hours at room temperature. The Si-Thiol product is
commercially available from Silicycle. The final palladium levels
for each of the palladium scavengers are shown in the table below.
TABLE-US-00005 Palladium Content Palladium Scavenger Following
Treatment (ppm) 10% L-cysteine on silica alumina 201 15% L-cysteine
on silica alumina 234 10% L-cysteine on silica gel 324 Si-Thiol
(Silicycle) 165, 217 TMT-silica gel 218
Example 11
Palladium Removal Using a Fixed Bed Reactor
[0069] Due to the difficulty in handling the slurry when using a
batch stirring procedure, and because the subsequent filtration is
slow, a new method of treating a palladium contaminated solution
using a fixed bed reactor was employed. Compound 3, described
previously in Example 4, was used to test a palladium removal
process using cysteine-adsorbed silica gel in a fixed bed reactor.
After compound 3 was synthesized, the crude reaction mixture was
filtered through filter paper and washed with THF (500 mL) to
afford a dark solution. The filtered reaction mixture was diluted
with 2L of THF to avoid solids precipitating out after palladium
removal. Prior to treatment, the palladium content was 4170 ppm.
The experimental setup for the palladium removal process using a
fixed-bed reactor is shown in FIG. 1. The reservoir contained 80 mL
of the reaction mixture. The fixed bed reactor was packed with
cysteine-adsorbed silica gel in a column (1.times.15 cm). The
column contained 7.4 g of cysteine-adsorbed silica gel (5 wt. eq.
of compound 3 in every run). The fixed-bed reactor used in this
experiment was a shell-and-tube type reactor that allowed for the
passage of a cooling medium on the outside of the column, as shown
FIG. 1. Typical pressure drop over the small scale column was in
the range of 6 to 8 psi at a flow rate of 1 g/min. A UV-vis
detector was used in some experiments to monitor the color change
in the solution, where a wavelength of 700 nm was used. FIG. 2
shows a comparison of the UV-vis signal when passing solutions of
constant concentration through plain silica gel (Merck 10810) and
cysteine-adsorbed silica gel (cysteine adsorbed to Merck 10810
silica gel). The color change was not only caused by palladium
removal, but also by dark-colored impurities removed by silica gel
itself during the treatment process. The difference between the two
curves in FIG. 2 is believed to show the kinetics of palladium
removal by cysteine. It can be seen that palladium removal was
rapid during the initial 10 minutes, but quickly slowed to almost
undetectable rates. An explanation for thie initial rapid
palladium-removal rate was that some cysteine was easily accessible
(e.g. cysteine on the outer layer of the silica gel, or in the
larger pores). After the easily accessible cysteine was consumed,
the rate of palladium removal by cysteine-adsorbed silica gel was
so slow that it was not easily detected. This observation suggests
that the controlling step of this reaction was the diffusion of
palladium-bonded molecules into the silica gel matrix.
[0070] The profiles of palladium concentration as a function of
recirculation time are shown in FIG. 3, in which the reaction
mixture was pumped through a fixed bed reactor containing 5 wt.
equivalents of cysteine-adsorbed silica gel. FIG. 3 indicates that
the palladium concentration reduced sharply during the first two
hours, after which the reduction rate slowed considerably. Further
results are shown in the table below, which compares different
operating conditions for the fixed bed reactor to the batch
stirring process. The results of runs 1 and 2 indicate that the
batch stirring process is comparable in effectiveness to the fixed
bed for palladium removal. These results also indicate that
doubling the amount of cysteine-adsorbed silica gel (run 3) or
double treatment (run 4) reduced palladium concentration to the
same level. TABLE-US-00006 Amount of Palladium Cysteine-Adsorbed
Content Run Process Silica Gel (equiv.) Time (hours) (ppm) 1 Batch
stirring 5 15 352 2 Fixed bed 5 15 386 3 Fixed bed 10 15 167 4
Fixed bed 1.sup.st 5 8 812 2.sup.nd 5 8 158
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